Date

2016

Department or Program

Chemistry

Primary Wellesley Thesis Advisor

David Haines

Additional Advisor(s)

Megan Nunez

Additional Advisor

Jim Moyer

Additional Advisor

Courtney Coile

Abstract

Glugacon-like-peptide-1 receptor (GLP-1R) is a G protein-coupled receptor located on the β-cells of the pancreas. When the incretin hormone, glucagon-like-peptide-1 (GLP-1), binds to GLP-1R, it triggers intracellular signaling cascades that lead to insulin release from pancreatic β-cells. However, the half-life of GLP-1 in plasma is less than two minutes, which makes GLP-1 ineffective to administer as a drug for treatment of abnormal glucose levels. Previous studies have investigated GLP-1R agonists for use of glucose-lowering therapy. T-0632, a non-peptidic small molecule, is an inverse agonist of GLP-1R. Understanding the molecular interactions of binding between T-0632 and GLP-1R within the binding pocket can provide deeper insights to drug design for diabetes treatment. In order to achieve this, we want to create a library of T-0632 analogs possessing an azido group in a variety of locations around the molecule. Azido-analogs of T-0632, prepared through iodine displacement, will allow photolabeling studies of these interactions. We have focused on generating azide substitutions on the isoquinoline moiety of T-0632. Iodination of a tetrahydroisoquinoline has given three of four possible iodinated products, as confirmed by initial mass spectrometry results. Oxidation of this isoquinoline results in the isoquinoline precursor to the iodinated T-0632.

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